The present invention relates to a genus of substituted cyclic ureas and derivatives thereof useful as antagonists of tachykinin receptors, in particular as antagonists of the neuropeptides neurokinin-1 receptor (NK1).
Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example respiratory diseases such as chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough, bronchospasm; inflammatory diseases such as arthritis and psoriasis; skin disorders such as atopic dermatitis and contact dermatitis; ophthalmological disorders such as retinitis, ocular hypertension and cataracts; addictions such as alcohol dependence and psychoactive substance abuse; stress related disorders such as post traumatic stress disorder; obsessive/ compulsive disorders; eating disorders such as bulemia, anorexia nervosa and binge eating disorders; mania; premenstrual syndrome; central nervous system conditions such as anxiety, general anxiety disorder, panic disorder, phobias, bipolar disorders, migraine, epilepsy, nociception, emesis, depression, psychosis, schizophrenia, Alzheimer""s disease, AIDs related dementia and Towne""s disease; gastrointestinal disorders such as Crohn""s disease and colitis; nausea; bladder disorders; atherosclerosis; fibrosing disorders; obesity; Type II diabetes; pain related disorders such as neuropathic pain, post-operative pain, headache and chronic pain syndromes; and genitourinary disorders such as interstitial cystitis and urinary incontinence.
In particular, NK1 receptors have been reported to be involved in microvascular leakage and mucus secretion, making NK1 receptor antagonists especially useful in the treatment and prevention of asthma, emesis, nausea, depression, anxiety, cough, pain and migraine.
Compounds of the present invention are represented by the formula I 
or a pharmaceutically acceptable salt thereof, wherein
Ar1 and Ar2 are independently selected from the group consisting of R17xe2x88x92 heteroaryl and 
X1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, NR12xe2x80x94, xe2x80x94N(COR12)xe2x80x94 or xe2x80x94N(SO2R15)xe2x80x94;
R1, R2, R3 and R7 are each independently selected from the group consisting of H, C1-C6 alkyl, hydroxy(C1-C3)alkyl, C3-C8 cycloalkyl, xe2x80x94CH2F, xe2x80x94CHF2 and xe2x80x94CF3; or R1 and R2, together with the carbon to which they are attached, form a C3-C6 alkylene ring; or, when X1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR12xe2x80x94, R1 and R2 together are xe2x95x90O;
each R6 is independently selected from H, C1-C6 alkyl, xe2x80x94OR13 or xe2x80x94SR12;
n is 1-4, if n is greater than 1, then R6 and R7 can be the same or different on each carbon; 
xe2x80x83is selected from the group consisting of 
X2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR5xe2x80x94;
Y is xe2x95x90O, xe2x95x90S or xe2x95x90NR11;
Y1 is H, C1-C6 alkyl, xe2x80x94NR17R13, xe2x80x94SCH3, R19-aryl(CH2)n6xe2x80x94, R19-heteroaryl-(CH2)n6xe2x80x94, xe2x80x94(CH2)n6-heterocycloalkyl, xe2x80x94(C1-C3)alkyl-NHxe2x80x94C(O)O(C1-C6)alkyl or xe2x80x94NHC(O)R15;
R5 is H or xe2x80x94(CH2)n1xe2x80x94G, wherein n, is 0-5, G is H, xe2x80x94CF3, xe2x80x94CHF2, xe2x80x94CH2F, xe2x80x94OH, xe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94SO2R13, xe2x80x94Oxe2x80x94(C3-C8 cycloalkyl), xe2x80x94NR13R14, xe2x80x94SO2NR13R14, xe2x80x94NR13SO2R15, xe2x80x94NR13COR12, xe2x80x94NR12(CONR13R14), xe2x80x94CONR13R14, xe2x80x94COOR12, C3-C8 cycloalkyl, R19-aryl, R19-heteroaryl, 
xe2x80x83or when n, is 0, R5 can also be xe2x80x94C(O)R13 or xe2x80x94C(S)R13; provided that G is not H when n1=0;
X is xe2x80x94NR20xe2x80x94, xe2x80x94N(CONR13R14)xe2x80x94, xe2x80x94N(CO2R13)xe2x80x94, xe2x80x94N(SO2R15)xe2x80x94, xe2x80x94N(COR12)xe2x80x94, N(SO2NHR13)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94CF2xe2x80x94, xe2x80x94CH2xe2x80x94 or xe2x80x94CR12Fxe2x80x94;
R8, R9 and R10 are independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, xe2x80x94OR12, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94CHF2, xe2x80x94CH2F, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2F, xe2x80x94COOR12, xe2x80x94CONR21R22, xe2x80x94NR21COR12, xe2x80x94NR21CO2R15, xe2x80x94NR21CONR21R22; xe2x80x94NR21SO2R15, xe2x80x94NR21R22, xe2x80x94SO2NR21R22, xe2x80x94SR(O)n5R15, R16-aryl and R19-heteroaryl;
R11 is H, C1-C6 alkyl, C3-C8 cycloalkyl, xe2x80x94NO2, xe2x80x94CN, OH, xe2x80x94OR12, xe2x80x94O(CH2)n6R12; xe2x80x94(C1-C3)alkyl-C(O)NHR12, R19-aryl(CH2)n6xe2x80x94 or R19-heteroaryl(CH2)n6xe2x80x94;
R4 and R12 are each independently selected from the group consisting of H, C1-C6 alkyl and C3-C8 cycloalkyl;
R13 and R14 are independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, R19-aryl(CH2)n6xe2x80x94 or R19-heteroaryl(CH2)n6xe2x80x94; or R13 and R14 together are C3-C6 alkylene and with the nitrogen to which they are attached form a 4-7 membered ring, or one of the carbon atoms in the alklyene chain formed by R13 and R14 is replaced by a heteroatom selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR12xe2x80x94;
R15 is C1-C6 alkyl, C3-C8 cycloalkyl or xe2x80x94CF3;
R16 is 1 to 3 substituents independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halogen and xe2x80x94CF3;
R17 is H, C1-C6 alkyl, C3-C8 cycloalkyl, xe2x80x94COOR12, xe2x80x94CONR21R22, xe2x80x94NR21R22, xe2x80x94NR21COR12, xe2x80x94NR2CO2R12, xe2x80x94NR21CONR21R22, xe2x80x94NR21SO2R15 or xe2x80x94S(O)n5R15;
R18 is H, C1-C6 alkyl or xe2x80x94P(O)(OH)2;
R19 is 1 to 3 substituents independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, xe2x80x94OH, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94CHF2, xe2x80x94CH2F, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2F, xe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94(C3-C8 cycloalkyl), xe2x80x94COOR12, xe2x80x94CONR21R22, xe2x80x94NR21R22, xe2x80x94NR21COR12, xe2x80x94NR21CO2R12, xe2x80x94NR21CONR21R22, xe2x80x94NR21SO2R15 and xe2x80x94S(O)n5R15;
R20 is H, C1-C6 alkyl, C3-C8 cycloalkyl or xe2x80x94(CH2)n6-heterocycloalkyl;
R21 and R22 are independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl and benzyl; or R21 and R22 together are C3-C6 alkylene and with the nitrogen to which they are attached form a 4-7 membered ring, or one of the carbon atoms in the alklyene chain formed by R21 and R22 is replaced by a heteroatom selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR12xe2x80x94;
R23, R24, R25 and R26 are H, C1-C6 alkyl and can be together as xe2x95x90O; when n5=0, and R25 and R26xe2x95x90H, X is not O, N, S;
n3 and n4 are independently 1-5, provided that the sum of n3 and n4 is 2-6;
n5 is independently 0-2;
n6 is independently 0-3; and
q and r are independently 1 or 2.
Preferred are compounds of formula I wherein R4 and R7 are each H. Also preferred are compounds of formula I wherein R1 and R3 are each H. Also preferred are compounds of formula I wherein R1, R3, R4 and R7 are each H. R6 is preferably H or xe2x80x94OH. Preferably, X1 is xe2x80x94Oxe2x80x94 or xe2x80x94NR12xe2x80x94. Ar1 and Ar2 are each preferably R8, R9, R10-phenyl, wherein R8, R9 and R10 are independently selected. Y is preferably xe2x95x90O, and n is preferably 1 or 2. When Y is xe2x95x90O, X2 is preferably xe2x80x94NR5xe2x80x94. More preferred are compounds of formula I wherein Q is xe2x80x94X2xe2x80x94C(xe2x95x90Y)xe2x80x94NR4xe2x80x94 (i.e., the first structure shown in the definition of Q), R1, R3, R4 and R7 are each H; R6 is H or xe2x80x94(CH2)n1xe2x80x94G, G is not H when n1=0; R19-heteroaryl. Most preferred are compounds of formula I wherein R5 is H.
This invention also relates to the use of a compound of formula I in the treatment of, for example, respiratory diseases such as chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough, broncospasm; inflammatory diseases such as arthritis and psoriasis; skin disorders such as atopic dermatitis and contact dermatitis; opthalmalogical disorders such as retinitis, ocular hypertension and cataracts; addictions such as alcohol dependence and psychoactive substance abuse; stress related disorders such as post traumatic stress disorder; obsessive/compulsive disorders; eating disorders such as bulimia, anorexia nervosa and binge eating disorders; mania; premenstrual syndrome; central nervous system conditions such as anxiety, general anxiety disorder, panic disorder, phobias, schizophrenia, Alzheimer""s disease, AIDs related dementia and Towne""s disease; gastrointestinal disorders such as Crohn""s disease and colitis; nausea; bladder disorders; atherosclerosis, fibrosing disorders; obesity; Type II diabetes; pain related disorders such as neuropathic pain, post-operative pain, headache and chronic pain incontinence. The treatment of mammals, both human and non-human, is contemplated.
Further, the invention relates to a method for antagonizing the effect of Substance P at its receptor site or for the blockade of neurokinin-1 receptors in a mammal, comprising administering an amount of a compound of formula I effective to antagonize the effect of Substance P at its receptor site in a mammal in need of such treatment.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I in a pharmaceutically acceptable carrier. The invention also relates to the use of said pharmaceutical composition in the treatment of the mammalian disease states listed above.
The compounds of this invention can be combined with a selective serotonin reuptake inhibitor (SSRI) (i.e., the compounds of this invention can be combined with an SSRI in a pharmaceutical composition, or the compounds of this invention can be administered with an SSRI.
Numerous chemical substances are known to alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation of neuronally released serotonin. Representatives SSRIs include, without limitation; fluoxetine, fluvoxamine, paroxetine and sertaline, and pharmaceutically acceptable salts thereof. Other compounds can readily be evaluated to determine their ability to selectively inhibit serotonin uptake.
In another aspect, the invention relates to a method of treating the above diseases and disorders comprising administering an effective amount of an NK1antagonist of formula I in combination with an SSRI described above.
In another aspect, the invention relates to a method of treating the above diseases and disorders comprising administering an effective amount of an NK1 antagonist of formula I in combination with an SSRI selected from: fluoxetine, fluvoxamine, paroxetine and sertaline, and pharmaceutically acceptable salts thereof.
In another aspect, the invention relates to a method of treating emesis, depression, anxiety, and cough comprising administering an effective amount of an NK1 antagonist of formula I in combination with an SSRI described above.
In the methods of this invention wherein a combination of an NK1 antagonist of this invention (compound of formula I) is administered with an SSRI described above, the compound of formula I and SSRI can be administered simultaneously, consecutively (one after the other within a relatively short period of time), or sequentially (first one and then the other over a period of time). In general, when the antagonists are administered consecutively or sequentially, the NK1 antagonist of this
Preferred are Compounds of Formula Ia and Ib 
wherein R8 is H or halogen, R2 is H, xe2x80x94CH2OH; R6 is H or xe2x80x94OH; and R5 is selected from the group consisting of hydrogen and groups of the formula xe2x80x94(CH2)n1xe2x80x94G as follows, 
or xe2x80x94(CH2)n1xe2x80x94Gxe2x80x2 wherein n1 is 2-4 and Gxe2x80x2 is H, xe2x80x94OH, xe2x80x94OCH3xe2x80x94, xe2x80x94OEt, xe2x80x94O(i-Pr), xe2x80x94O-cylclopropyl, or xe2x80x94CONR13R14, wherein R13 and R14 are independently selected from the group consisting of H, xe2x80x94CH3, Et, i-Pr, or cyclopropyl (Et is ethyl and i-Pr is isopropyl).
Also preferred are compounds of the formula Ic and Id 
wherein X1 is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94 or xe2x80x94N(COCH3)xe2x80x94; R8 is H or halogen; R2 is H, xe2x80x94CH3 or xe2x80x94CH2OH; R9 is xe2x80x94OCF3 or 5-(trifluoromethyl)-1H-tetrazol-1yl; R6 is H or xe2x80x94OH; R12 is xe2x80x94CH3 or cyclopropyl; and R5 is selected from the group consisting of hydrogen and groups of the formula xe2x80x94(CH2)n1xe2x80x94G as shown above for structures Ia and Ib.
Preferred compounds of the invention are the compounds of examples 2, 61, 79a, 79b, 92, 93, 126, 127, 128, 129, 165a, 165b, 166a and 166b.
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched alkyl chains. xe2x80x9cLower alkylxe2x80x9d refers to alkyl chains of 1-6 carbon atoms and, similarly, lower alkoxy refers to alkoxy chains of 1-6 carbon atoms.
xe2x80x9cArylxe2x80x9d means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl. R16-aryl and R19-aryl refer to such groups wherein substitutable ring carbon atoms have an R16 or an R19 substituent.
xe2x80x9cHalogenxe2x80x9d refers to fluoro, chloro, bromo or iodo atoms.
xe2x80x9cHeteroarylxe2x80x9d refers to 5- to 10-membered single or benzofused aromatic rings comprising 1 to 4 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Nxe2x95x90 and xe2x80x94NHxe2x80x94, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single-ring heteroaryl groups are furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. Examples of benzofused heteroaryl groups are benzimidazolyl, benzofuranyl, benzo-thiophenyl, benzoxazolyl, indolyl and quinolyl. N-oxides of nitrogen-containing heteroaryl groups are also included. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl, and when R4 or R5 is heteroaryl, it can be joined to the nitrogen atom of the xe2x80x9cxe2x80x94Qxe2x80x94xe2x80x9d group either by a ring carbon or a ring nitrogen. R19-heteroaryl refer to such groups wherein substitutable ring carbon atoms have an R19 substituent. When R8, R9 or R10 is heteroaryl, it is preferable tetrazolyl substituted by H, C1-C4 alkyl, C3-C8 cycloalkyl, xe2x80x94CF3xe2x80x94SO2xe2x80x94(C1-C6 alkyl) or xe2x80x94OCF3.
xe2x80x9cHeterocycloalkylxe2x80x9d refers to a 4- to 7-membered saturated ring comprising 1 to 3 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR21xe2x80x94, wherein R21 is H or C1-C6 alkyl, and wherein the remaining ring members are carbon. Where a heterocyclic ring comprises more than one heteroatom, no rings are formed where there are adjacent oxygen atoms, adjacent sulfur atoms, or three consecutive heteroatoms. Examples of heterocyclic rings are tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.
In the above definitions, wherein variables R1 to R26 are said to be independently selected from a group of substituents, we mean that R1, R2, R3, etc., are independently selected, but also that where an R8, for example, occurs more than once in a molecule, those occurrences are independently selected (e.g., if X1 is xe2x80x94NR12xe2x80x94 wherein R12 is hydrogen, G can be xe2x80x94COOR12 wherein R12 is methyl). Similarly, R8, R9 and R10 can be independently selected from a group of substituents, and where more than one R8, R9 or R10 is other than hydrogen, the substituents are independently selected; those skilled in the art will recognize that the size and nature of the substituent(s) will affect the number of substituents which can be present.
The xe2x80x9cQxe2x80x9d groups are always joined to the rest of the molecule as shown, i.e., they are attached left-to-right, where xe2x80x94X2xe2x80x94 or xe2x80x94NR5xe2x80x94 is attached to the carbon to which R6 and R7 are attached, and xe2x80x94NR4xe2x80x94 is always attached to the carbon to which Ar1 is attached.
Compounds of formula I can have at least one asymmetrical carbon atom and all isomers, including diastereomers, enantiomers and rotational isomers are contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I.
Those skilled in the art will appreciate that for some compounds of formula I, one isomer will show greater pharmacological activity than other isomers.
Compounds of the invention which have an amino group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, tartaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.
Certain compounds of the invention which are acidic (e.g., those compounds which possess a carboxyl group) form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Compounds of formula I can be prepared using methods known to those skilled in the art. Typical procedures are described below, although the skilled artisan will recognize that other procedures may be applicable, and that the procedure may be suitably modified to prepare other compounds within the scope of formula I.
Compounds of formula I wherein X1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and n is 1 can be prepared by the following method. 
An alcohol (3), in which Ar1 and R3 are as defined above is converted to the ketone (2), by reaction with an activated derivative (1) of the alcohol (4), in which Ar2, R1 and R2 are as defined above. 
This reaction is most favorable when R1, R2 and R3 are each H but, depending on the leaving group L, it may work effectively if either R1, R2 or R3 is C1-C6 alkyl. A leaving group, L, of choice is CF3SO2xe2x80x94 (triflate) but others also suffice, such as Br or I. The base used may vary but is preferably one of the hindered non-nucleophilic kind, of which an example is 2,6-di-tert-butyl-4-methyl pyridine.
The alkylating agent (3a) in which L is triflate may be prepared from the alcohol-type starting material (4) using triflic anhydride and the same hindered, non-nucleophilic base as is used for the alkylation.
The ketone (2) may be used to prepare compounds in which n is 1, X2 is xe2x80x94NR5xe2x80x94 and Y is xe2x95x90O (5). Reaction of (2) with a metallic cyanide (e.g. KCN) and (NH4)2CO3 results in the formation of the hydantoin, a process well known to those skilled in the art of organic synthesis: 
Selective reduction of the amide carbonyl and not the urea carbonyl may be accomplished by using a mixture of lithium aluminum hydride (LAH) and AlCl3 as a preferred method although other methods are also available, such as the use of LAH in ether or THF at or above room temperature, up to the boiling point of the solution.
The reaction produces compounds of the invention in which R4 and R5 are both H. Introduction of a substituent, R5, may be performed relatively selectively although in some cases a second substituent R4 (where R4xe2x95x90R5 in this case) may be introduced at the same time. Such substitution reaction at the nitrogen atoms of (5) may be accomplished using one of many sets of conditions used for such transformations, for example, use of an organic base, such as triethylamine or Hunig""s Base (di-isopropyl ethylamine) and the appropriate alkylating agent, Lxe2x80x94R5.
Reaction of the hydantoin (5) with p-methoxybenzyl chloride in acetone in the presence of K2CO3 and a catalytic quantity of tetra-n-butylammonium iodide produces the derivative (5A) which can be readily reduced to a mixture of alcohols (5B) by use of mild reducing conditions. Suitable reagents are LAH in THF at 0-30xc2x0 C. for 1-6 hrs. 
Subsequent removal of the PMB protecting group may be carried out using Ce(NH4)2 (NO3)6 (CAN) in a neutral solvent, preferably a CH3CN/water mixture. The mixture of chiral alcohols can frequently be separated and purified by chiral HPLC, preferably on one of the carbohydrate-based columns, such as one of the Daicel Chiralcel(copyright) or Chiralpak(copyright) series of columns.
Compounds of formula I wherein X1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and Y is xe2x95x90O or xe2x95x90S can be prepared by the following method.
The ketone (2) may also be made by the following sequence of reactions. The alcohol (1) may be converted to its alkoxide anion using a strong base, such as lithium bis(trimethyl silyl)amide or the like, followed by reaction, in an inert solvent, such as THF, with the N,O-dimethyl amide of the iodo-acid (7) to produce (8) which is known as a xe2x80x9cWeinreb amidexe2x80x9d. 
Addition of an organometallic derivative of Ar1 (9) results in formation of the ketone (2). Suitable organometallic reagents include the Grignard (M is Mg) or lithium reagent. Suitable media for this reaction include neutral, non-reactive solvents such as ether or THF. 
The ketone (2) may next be reacted with trimethylsilylcyanide in the presence of a Lewis acid catalyst, such as znI2, and subsequently treated with saturated NH3xe2x80x94CH3OH at ambient temperature to yield an intermediate which may be reduced directly to diamine (10) using a powerful hydride reducing agent such as LAH in a neutral solvent such as THF. 
Reaction of the diamine (10) with a reagent known to introduce a carbonyl between two amines located in the correct position leads to the cyclic ureas (5) which are compounds of the invention. Examples of such reagents are COCl2, carbonyl diimidazole and methyl or ethyl chloroformate. Subsequent modification by introduction of R4 and R5 groups may be performed as described in Method 1.
The reaction described above can also be used to prepare compounds of the invention in which X1 is xe2x80x94Sxe2x80x94 by employing the thiol corresponding to the alcohol (4) shown above. In addition, reagents known to introduce the xe2x80x94C(xe2x95x90S)xe2x80x94 function between two appropriately placed nitrogen atoms (such as thiocarbonyl diimidazole) may be used to prepare compounds in which Y is xe2x95x90S.
A further use of compounds such as 10A is to introduce the guanidine functions into compounds of the invention. Reacting (10A) with CH3 I in a neutral solvent, such as CH3CN, THF, or a mixture of the two, produces the S-methyl derivative (10B) which may then be reacted with an amine, R11xe2x80x94NH2, to produce guanidines (10C) or a tautomer. 
The diamine (10) is also a useful intermediate for preparation of products of the invention in which X2 is xe2x80x94NR5xe2x80x94. The group R5 is introduced by use of an aldehyde or ketone precursor of R5 by a process of reductive amination (otherwise known as reductive alkylation of the amine (10)). A proviso of this method is that the R5 group may not contain a quaternary carbon atom next to the nitrogen atom. It also cannot be H, nor certain other of the definitions of R5, for example, when G is xe2x80x94OH, xe2x80x94SO2R13 or xe2x80x94NR13R14 etc., then n1 cannot be 0. To describe the process, the starting material (10D) will be used. By reacting (10) with (10D) in a neutral solvent, such as 1,2-dichloroethane, in the presence of a suitable reducing agent (sodium triacetoxy-borohydride is particularly suitable for this reaction), and conventional work-up, a product (10E) is formed (R5 is xe2x80x94(CH2)n1xe2x80x94G in which n1 is 0 and G is 
in which n3=n4=2 and X=0:
A variable amount of the isomeric structure (10F) (see above) may also form in this reaction, depending upon the reactants. It may be separated from (10E) by conventional chromatographic methods and reacted, as above, to yield compounds of the invention in which R4 is the introduced substituent instead of R5.
Reactions with other precursors of the R6 group are also possible, as will be evident to one skilled in the arts of organic and medicinal chemistry. Ring closing of (10E) may be carried out by direct cyclization to make many of the Q groups of the invention in which an R5 group is present and where Y is =0 or xe2x95x90S, or compounds wherein Y is xe2x95x90Nxe2x80x94R5 can be made by the sequence of reactions described earlier for the synthesis of (10C).
A further use for the diamine (10) is in the preparation of compounds of the invention in which Y1 is as defined above, except that it is not xe2x80x94NH2, xe2x80x94NHCH3 or xe2x80x94SCH3. The diamine (10) may be heated with a carboxylic acid, Y1xe2x80x94CO2H, in a high boiling, neutral solvent, such as toluene to produce the amidines (10G) of the invention: 
An alcohol (3) may be reacted with an O-substituted hydroxylamine derivative, preferably methoxylamine to yield the oxime derivative (11). Conversion of the oxime to the alkoxide may be performed using a strong base, such as NaH, in a non-hydroxylic solvent, such as THF. Reaction of this anion with the substituted alkyl halide (12), in which Hal is preferably I or Br, produces the oxime-ether (13). 
Cleavage of the oxime-ether (13) under acidic conditions, for instance, using 6N HCl at elevated temperature for 5 to 50 hours results in isolation of the ketone (2).
Further processing of (2) may be performed as described above in Method 1.
Compounds of formula I wherein X1 is xe2x80x94Oxe2x80x94 and n is 2-4 can be prepared by the following method (only R6 is shown in the formulae, but both R6 and R7 can be present).
A diprotected aryl glycine ester, such as (14), in which xe2x80x9cProtxe2x80x9d is a protecting group, preferably benzyl, and xe2x80x9cExe2x80x9d is an ester group, preferably methyl or ethyl, may be converted to its anion using a strong base, such as lithium diisopropylamide, in an ether solvent, such as THF, at a temperature of about xe2x88x9278xc2x0 C. Reaction of the anion with a halo-nitrile (15), in which xe2x80x9cHalxe2x80x9d is preferably 1, at temperatures between xe2x88x9278xc2x0 C. and 0xc2x0 C. results in the protected intermediate (16). 
Reduction of the ester and nitrile simultaneously using a powerful hydride reducing agent, such as LAH, in an inert solvent, such as THF, at a temperature between about xe2x88x9278xc2x0 C. and 0xc2x0 C., produces aminoalcohol (17). 
Removal of the protecting groups under standard conditions (e.g. 20% Pd(OH)2 on active carbon in methanol if xe2x80x9cProtxe2x80x9d is benzyl) yields the di-amine alcohol (18) which may be cyclized using one of the reagents known to introduce a Cxe2x95x90O, Cxe2x95x90S or xe2x80x94SO2xe2x80x94 group between two appropriately placed nitrogen atoms (e.g. COCl2; carbonyl diimidazole; thiocarbonyl diimidazole, etc.) to yield (19). 
wherein xe2x95x90Y is xe2x95x90O or xe2x95x90S; the thio-urea can be prepared in a similar manner.
The alcohol (19) may be converted to a compound of the invention (20), by reaction of the mono-anion prepared by using a strong base, such as NaH, with a benzyl halide in the presence of Ag2O. xe2x80x9cHalxe2x80x9d is as defined above and the solvent is preferably a polar, non-hydroxylic solvent such as DMF. 
Subsequent modification by introduction of R4 and R5 groups may be performed as described in Method 1.
The intermediate (17), above, may also be converted to compounds of the invention via its di-BOC protected derivative (21).
Removal of the original protecting groups (if they are benzyl groups or similar) by hydrogenolysis in the presence of (BOC)2O yields the di-BOC derivative (21). 
Such intermediates may be converted to the ethers (22) by reaction with an aryl halide (23), preferably a bromide or iodide. Use of silver oxide (Ag2O) as a catalyst and base is desirable. 
Removal of the BOC protecting groups under standard conditions (e.g.
HCl/ether) produces the diamine which may be cyclized to compounds of the invention using the same reagents as described earlier in Method 2, e.g. COCl2, carbonyl diimidazole, sulfonyl diimidazole, etc.
Compounds of the invention in which X1 is one of the nitrogen-containing groups may be synthesized from the amino ketone derivatives (10G), some of which may be commercially available while others can be synthesized by well-known literature techniques. Protection of the amino group in (10G), for instance as its BOC derivative, allows the hydantoin-forming reaction to occur to produce intermediates (10H) where xe2x80x9cProtxe2x80x9d is the previously-introduced protecting group, e.g. BOC: 
Reduction of one of the carbonyl groups preferentially, as described previously, using the LiALH4/AlCl3 mixed reagents, followed by removal of the protecting group by an appropriate method (e.g., CF3CO2H or HCl if it is BOC) produces the amine (10I) 
Reductive alkylation of the amine group with an aldehyde or ketone (10J) under conditions described for this transformation earlier (using sodium triacetoxyborohydride) or using one of the many published procedures known to carry out this reaction (e.g. sodium borohydride in an alcohol solvent) results in the amine (10K) which may be further modified by reactions well known in the art to produce other compounds of the invention, (10L) and (10M). 
Reactive groups not involved in the above processes can be protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction. The following Table 1 shows some typical protecting groups:
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington""s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation for treatment of respiratory diseases; inflammatory diseases; skin disorders; ophthalmalogical disorders; addictions; stress related disorders; obsessive/compulsive disorders; eating disorders; mania; premenstrual syndrome; central nervous system conditions; gastrointestinal disorders; bladder disorders; atherosclerosis; fibrosing disorders; obesity; Type II diabetes; pain related disorders; and genitourinary disorders; may be varied or adjusted from about 1 mg to about 1500 mg, preferably from about 50 mg to about 500 mg, more preferably from about 20 mg to about 200 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 1500 mg/day, in two to four divided doses.
Following are examples of preparing compounds of formula I. As used herein, RT is room temperature, Me is methyl, Bu is butyl, Br is bromo, Ac is acetyl, Et is ethyl, Ph is phenyl, THF is tetrahydrofuran, EtOAc is ethyl acetate, Et2O is ether, LAH is lithium aluminum hydride, CDI is 1,1-Carbonyl diimidazole; HOBT is hydroxybenzotriazole; DEC is 1,2-diethylaminoethyl chloride; TFA is trifluoroacetic acid; Et3N is triethylamine, MTBE is t-butyl methyl ether; DAST is diethylaminosulfur trifluoride.